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Emerging therapies using human induced pluripotent stem cell (iPSCs)\u2010derived mesenchymal stem cells (iMSCs) show promise for IDD treatment. In this study, it is first demonstrated that senescent NP cells promote macrophage polarization toward the pro\u2010inflammatory M1 phenotype in coculture systems. Reciprocally, conditioned medium from M1 macrophages exposed to senescent NP cells accelerates senescence in healthy NP cells. Notably, it is identified that iMSCs\u2010derived exosomes break this pathogenic cycle by reprogramming M1 macrophages toward anti\u2010inflammatory M2 phenotypes. Mechanistically, these exosomes deliver miR\u2010100\u20105p to suppress mTORC1 signaling and regulate glycolysis metabolic reprogramming in macrophages. These findings are corroborated in a rat IDD model, where iMSC\u2010exosomes mitigate IDD progression in vivo. This work elucidates a novel iMSC\u2010exosomes mediated mechanism regulating macrophage\u2010NP cell interactions, which provides a promising therapeutic strategy for IDD intervention.<\/jats:p>","DOI":"10.1002\/advs.202504347","type":"journal-article","created":{"date-parts":[[2025,7,6]],"date-time":"2025-07-06T23:30:09Z","timestamp":1751844609000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Human iPSCs Derived MSCs\u2010Secreted Exosomes Modulate Senescent Nucleus Pulposus Cells Induced Macrophage Polarization via Metabolic Reprogramming to Mitigate Intervertebral Disc Degeneration"],"prefix":"10.1002","volume":"12","author":[{"given":"Qian","family":"Xiang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics Peking University Third Hospital  Beijing 100191 China"},{"name":"Engineering Research Center of Bone and Joint Precision Medicine Ministry of Education  Beijing 100191 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